Bisphosphonates Induce Apoptosis of Circulating Endothelial Cells in Multiple Myeloma Patients and in Subjects with Bisphosphonate-Induced Osteonecrosis of the Jaws

Allegra, Alessandro; Alonci, Andrea; Penna, Giuseppa; Granata, A; Siniscalchi, Enrico Nastro; Oteri, Giacomo; Loddo, Saverio; Teti, Diana; Cicciù, D; Ponte, Francesco Saverio De; Musolino, Caterina

doi:10.1159/000313787

Cited by 43 publications

(26 citation statements)

References 70 publications

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“…In patients with multiple myeloma (MM) and MRONJ, EC apoptosis was reported to increase following administration of BPs. This supports the hypothesis that BPs inhibit angiogenesis by interfering with EC proliferation and survival, leading to loss of blood vessels and avascular necrosis (Allegra et al 2010).…”

Section: Angiogenesis Vascularization and Endothelial Damagesupporting

confidence: 87%

Diabetes as a Risk Factor for Medication-Related Osteonecrosis of the Jaw

Peer¹,

Khamaisi²

2014

J Dent Res

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Medication-related osteonecrosis of the jaw (MRONJ) is a severe devastating complication for which the exact pathogenesis is not completely understood. Multiple systemic and local factors may contribute to the development of MRONJ. A growing body of evidence supports diabetes mellitus (DM) as an important risk factor for this complication; however, the exact mechanism by which DM may promote MRONJ has yet to be determined. The current review elucidates the role of DM in the pathogenesis of MRONJ and the mechanisms by which DM may increase the risk for MRONJ. Factors related to DM pathogenesis and treatment may contribute to poor bone quality through multiple damaged pathways, including microvascular ischemia, endothelial cell dysfunction, reduced remodeling of bone, and increased apoptosis of osteoblasts and osteocytes. In addition, DM induces changes in immune cell function and promotes inflammation. This increases the risk for chronic infection in the settings of cancer and its treatment, as well as antiresorptive medication exposure, thus raising the risk of developing MRONJ. A genetic predisposition for MRONJ, coupled with CYP 450 gene alterations, has been suggested to affect the degradation of medications for DM such as thiazolidinediones and may further increase the risk for MRONJ.

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Section: Angiogenesis Vascularization and Endothelial Damagesupporting

confidence: 87%

Diabetes as a Risk Factor for Medication-Related Osteonecrosis of the Jaw

Peer¹,

Khamaisi²

2014

J Dent Res

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“…[40] After bone remodeling alterations, the antiangiogenic activity of BPs has been suggested as one of the main determinants of the onset of ONJ [41,42]; the impact of VEGFR genetic polymorphism has also been investigated. [43] Further data have been obtained from studying the apoptosis of circulating endothelial cells following the treatment with BPs [44] and from several animal models. The role of tooth extraction or other alveolar trauma in the onset of ONJ is not entirely known although it may well be a possible trigger as well as a sentinel of pre-existing, underlying bone disease.…”

Section: Definition Of Onjmentioning

confidence: 99%

Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology

Fusco

Santini

Armento

et al. 2016

Expert Opinion on Drug Safety

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Introduction: Osteonecrosis of the jaw (ONJ) is a clinically important, potentially painful and debilitating condition, which can affect the quality of life of cancer patients. Since 2003, ONJ appeared as a Bisphosphonate(BP)-related class effect, and the term Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) was widespread. Areas Covered: Under discussion in this review is the fact that ONJ cases have been reported after treatment including antiangiogenic agents and other “targeted therapy”, with and without BPs. Consequently, the comprehensive term Medication-Related Osteonecrosis of the Jaw (MRONJ) has been introduced. The clinical aspects and the prognosis of ONJ associated with these new drugs are still less reported, but basing on their pharmacodynamics, they could be different from the well-known BRONJ. Accordingly, recommendations largely in use for BRONJ should be extended to these new forms, but critically applied and with respect to the individual risk assessment. Expert Opinion: There is a high risk of underdiagnoses for ONJ due to a lack of awareness, and too much restrictive or incomplete diagnostic criteria; at the same time, with regard to ONJ associated to the new non –antiresorptive agents, described here, we observe the strong need to improve the defining of any distinguished feature in their diagnosis, prevention and therapy

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“…In these patients, circulating endothelial cells are reduced in number and more apoptotic events are observed when compared with healthy controls. Furthermore, a correlation is seen between apoptotic cells and duration of bisphosphonate treatment [11]. Moreover, cancer patients demonstrate decreased levels of circulating vascular endothelial growth factor (VEGF) following zoledronate treatment, suggesting an inhibitory effect on angiogenesis [53].…”

Section: Angiogenesis Is Inhibited By Bisphosphonate Administrationmentioning

confidence: 99%

“…The rationale for the use of bisphosphonates in the cancer patient is to stabilize bones affected by metastatic or primary neoplastic disease involving bone and in treating hypercalcemia of malignancy [10]. Additionally, these drugs may have antiangiogenic effects that inhibit tumor growth and direct toxic effects on tumor cells [11][12][13][14][15]. More cases of ONJ associated with the oral bisphosphonates alendronate, risedronate, and ibandronate are being diagnosed and are likely related to cumulative dose effects [9,16].…”

Section: Introductionmentioning

confidence: 99%

Bisphosphonates and Osteonecrosis of the Jaws: A Review of Clinical Features and the Drug Effect on Oral Soft Tissues

Kramer

Fantasia

2011

Clinic Rev Bone Miner Metab

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The beneficial effects of the nitrogen-containing bisphosphonate drugs have been clearly defined, especially for the treatment for osteoporosis, metastatic or primary bone malignancies, and some rare bone diseases. The adverse effects of these drugs on oral hard and soft tissues are significant and recognized with increasing frequency. The clinical, radiographic, and histopathologic features of osteonecrosis of the jaws (ONJ) are well characterized; the effects of bisphosphonates on oral soft tissues are an emerging area of study. This review will provide an overview of ONJ from a clinical perspective and also discuss recent findings related to bisphosphonateinduced soft tissue pathology.

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Bisphosphonates Induce Apoptosis of Circulating Endothelial Cells in Multiple Myeloma Patients and in Subjects with Bisphosphonate-Induced Osteonecrosis of the Jaws

Cited by 43 publications

References 70 publications

Diabetes as a Risk Factor for Medication-Related Osteonecrosis of the Jaw

Diabetes as a Risk Factor for Medication-Related Osteonecrosis of the Jaw

Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology

Bisphosphonates and Osteonecrosis of the Jaws: A Review of Clinical Features and the Drug Effect on Oral Soft Tissues

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